Abstract

Objectives The aim of this study was to compare clinical outcomes in relation to the duration of triple antithrombotic therapy (TAT) among patients with indications for oral anticoagulation undergoing percutaneous coronary intervention (PCI).

Background TAT is recommended for patients undergoing PCI with a firm indication for oral anticoagulation. Duration of TAT may influence outcomes, but the optimal period of TAT remains uncertain.

Conclusions One-month TAT, used preferentially in patients with higher estimated bleeding risk in this observational study, was associated with similar net clinical outcomes compared with longer TAT durations throughout 1 year following PCI.

Up to 10% of patients undergoing percutaneous coronary intervention (PCI) have concomitant indications for oral anticoagulation (OAC) (1,2). The therapeutic targets of OAC protecting against ischemic complications related to fibrin-rich thrombus in patients with atrial fibrillation (AF) or mechanical valves (3,4) versus dual-antiplatelet therapy (DAPT) for prevention of platelet-dependent stent thrombosis (5,6) are complementary and dependent on different pathobiological pathways. Therefore, a combination of OAC plus DAPT is plausible among patients with indications for OAC undergoing PCI and is currently recommended in consensus documents (1,7–9). Triple antithrombotic therapy (TAT), the combination of OAC and DAPT, is associated with increased bleeding risk (10,11) but is more effective than DAPT alone for reduction of major adverse cardiovascular events in these patients (1,12,13).

Less intensive antithrombotic regimens (e.g., omission of aspirin) have received attention as a potential means of mitigating bleeding risk (14–16) and may be considered as an alternative to TAT in selected patients (1,7,8). Abbreviated regimens of TAT may be explored as an alternative strategy to optimize the benefit-to-risk ratio in view of the fact that bleeding associated with TAT appears to be exposure dependent and related to treatment duration (17). In this context, the ISAR-TRIPLE (Intracoronary Stenting and Antithrombotic Regimen–Testing of a 6-Week Versus a 6-Month Clopidogrel Treatment Regimen in Patients With Concomitant Aspirin and Oral Anticoagulant Therapy Following Drug-Eluting Stenting) randomized trial reported comparable net clinical outcomes with 6-week versus 6-month TAT following PCI with drug-eluting stent (DES), supporting the role of shorter TAT duration in this setting (18). The length of TAT is currently recommended to be adjusted according to individual thrombotic and bleeding risk, clinical presentation, and type of stent; these recommendations remain largely consensus rather than evidence based, as reflected by the low level of evidence and differences between European (1,7,8) and North American guidelines regarding specific TAT durations (19).

Against this background, the purpose of the present observational study was to compare clinical outcomes in relation to a regimen of 1-month versus more prolonged TAT in a cohort of unselected patients undergoing PCI with indications for OAC.

Methods

Patient population

This was a retrospective analysis of prospectively collected data. All consecutive patients undergoing PCI for stable coronary artery disease (CAD) or acute coronary syndrome (ACS) at Bern University Hospital (Bern, Switzerland) as of 2009 were prospectively entered into the Bern PCI Registry (NCT02241291). The present analysis included all consecutive patients with clinical indications for OAC who were discharged on TAT. Per default, most patients requiring OAC at our institution receive additional DAPT of differing duration following PCI instead of less intensive antithrombotic regimens (e.g., OAC plus antiplatelet monotherapy). In line with the inclusive character of the registry, there were no formal exclusion criteria. Demographic and clinical characteristics, information on performed interventions, and hospital outcome data were systematically collected. Scores of HAS-BLED (hypertension, abnormal liver or renal function, stroke or thromboembolism, bleeding history, elderly [age >65 years], drug consumption or alcohol abuse) were calculated, excluding labile international normalized ratio values, which were not collected. The registry was approved by the institutional ethics committee, and patients provided written informed consent to undergo prospective follow-up.

Procedures

PCI was performed in accordance with current practice guidelines (7). Periprocedural management, including interrupted versus uninterrupted OAC, dose of unfractionated heparin, or use of glycoprotein IIb/IIIa inhibitors, was left to the discretion of the operator. DAPT consisting of acetylsalicylic acid and a P2Y12 inhibitor was initiated before, at the time of, or immediately after the procedure. The P2Y12 inhibitor of choice was clopidogrel in the majority of patients. Ticagrelor or prasugrel was administered if deemed clinically necessary by the treating physician in certain cases of ACS, complex anatomy, or complicated interventions; prasugrel was selectively used before the excessive bleeding risk for TAT including prasugrel was reported (20). The duration of DAPT was not uniformly specified but individualized accounting for each patient’s clinical presentation, ischemic and bleeding risk profile.

Patient follow-up

Patients were systematically followed at discharge and throughout 1 year to assess adverse cardiac and cerebrovascular events. Survival data were obtained from hospital records and municipal civil registries. A health questionnaire was sent to all living patients with questions on rehospitalization, medical treatment, and adverse events, followed by telephone contact in case of missing response. General practitioners, referring cardiologists, and patients were contacted, and external medical records, discharge letters, and coronary angiography documentation were systematically reviewed as necessary for additional information. Medical treatment was recorded during index PCI, at discharge, and at 1 year.

Clinical endpoints and study assessments

A clinical event committee consisting of 2 cardiologists (and in case of disagreement of a third referee) adjudicated all events using original source documents. Cardiac death was defined as any death due to an immediate cardiac cause, procedure-related mortality, and death of unknown cause. Stent thrombosis and myocardial infarction (MI) were defined according to the Academic Research Consortium criteria (21) and the modified historical definition (22), respectively. Stroke was defined as rapid development of clinical signs of focal or global disturbance of cerebral function lasting >24 h with imaging evidence of acute, clinically relevant brain lesion. Bleeding events were categorized according to the Bleeding Academic Research Consortium (BARC) and TIMI (Thrombolysis In Myocardial Infarction) classifications (23).

For this analysis, patients were categorized into those discharged with 1-month versus more prolonged (>1 month) TAT following PCI. Categorization was based on prescription times at discharge and not actual duration of treatment. The primary endpoint was a composite of cardiac death, MI, stroke, definite stent thrombosis, or TIMI major bleeding. The rationale for a combined ischemic and bleeding endpoint is in line with the primary assessment of the ISAR-TRIPLE trial (18) (currently the only randomized trial comparing different TAT durations post-PCI), recognizing that both ischemic and bleeding complications adversely affect prognosis following PCI (24). The secondary bleeding endpoint was BARC ≥3 bleeding; the secondary ischemic endpoint was the composite of cardiac death, MI, stroke, or definite stent thrombosis.

The main analysis compared outcomes within 12 months in relation to prescribed TAT duration. Exploratory analyses included: 1) landmark analyses set at 30 days (i.e., focusing on the period after expected TAT cessation in the short-duration group); 2) sensitivity analyses excluding patients with ST-segment elevation MI as well as those receiving prasugrel or ticagrelor; and 3) stratified analyses in relation to stent type and clinical presentation.

Statistical analyses

Statistical analyses were performed with Stata version 14.0 (StataCorp LP, College Station, Texas). Continuous variables are summarized as mean ± SD or median (interquartile range) and categorical variables as actual numbers and percentages. Baseline and procedural characteristics and medications were compared using Fisher exact tests for binary responses, chi-square tests for more than 2 responses, unpaired Student t tests for means, and Mann-Whitney U tests for medians. Clinical outcomes were analyzed using Cox regression analysis (time to first event). All adjusted models were based on 20 datasets created using chained equations to impute missing date (estimates combined using Rubin’s rule). Subsequently, adjustment was made for the following baseline covariates: sex, clinical presentation with ACS, HAS-BLED score, use of any DES, and multiple-lesion treatment. Findings were considered statistically significant at the 0.05 level.

Results

Between March 2009 and December 2013, 8,772 consecutive patients undergoing PCI were included in the Bern PCI Registry. Of 568 patients with clinical indications for OAC who received TAT, 245 (43.1%) were discharged on TAT for 1 month and 323 (56.9%) for >1 month (median 3 months; interquartile range: 3 to 6 months) (Figure 1).

Procedural characteristics during the index intervention are shown in Table 2. The majority of patients (n = 448 [79%]) received new-generation DES. Patients with 1-month TAT were more commonly treated with bare-metal stents (BMS) or balloon angioplasty without stents. Medication use during index procedure, at discharge, and at 1-year follow-up is summarized in Table 3. Patients with 1-month versus longer term TAT less frequently received glycoprotein IIb/IIIa inhibitors during the index procedure, more commonly received clopidogrel, and less frequently received prasugrel at discharge.

Clinical Outcomes Within 1 Year in Relation to Prescribed Duration of Triple Antithrombotic Therapy

The primary endpoint did not differ significantly in relation to TAT duration in exploratory analyses stratified for stable CAD versus ACS (p for interaction = 0.18), PCI with or without DES (p for interaction = 0.95), and AF as the primary indication for OAC (p for interaction = 0.55) (Figure 5). Similarly, no difference was observed in stratified analyses for the secondary ischemic and bleeding endpoints (Figure 5) and for TIMI major bleeding (Online Figure 1).

Discussion

Although TAT is currently recommended for patients with indications for OAC who undergo PCI, optimal duration of TAT treatment is not well established (1). The main finding of this observational study is that an abbreviated, 1-month duration of TAT, determined by treating physicians according to individual patient risk profiles, was associated with similar bleeding and ischemic complications and net clinical outcomes throughout 1 year compared with more prolonged TAT regimens. Notwithstanding inherent limitations of nonrandomized investigations, these findings add to evidence indicating that shorter, patient-tailored DAPT durations assume a role in the management of orally anticoagulated patients undergoing coronary interventions (18). They also support current, largely consensus-based recommendations regarding the length of TAT treatment in this specific clinical setting (1,7–9,19).

In patients who require OAC and receive coronary stents, balancing the ischemic versus bleeding hazard remains a challenging task. Long-term TAT increases the risk for bleeding, including major and fatal bleeding (14–16,25), but may be more effective and in selected studies appeared to improve patient outcomes compared with DAPT alone (12,13). However, the occurrence of stent thrombosis tends to cluster within the early period following PCI (26,27), emphasizing the need for adequate antiplatelet protection early post-PCI. Current recommendations advocate patient-tailored reduction of TAT duration and specifically to 1 month in patients at high bleeding risk (e.g., HAS-BLED score ≥3) or presenting with stable CAD (1,7,8). Our finding of similar net clinical outcomes with short (1-month) compared with longer TAT adds new evidence in support of expert consensus statements and consistent guidelines (1,7–9,19). These results held true after multivariate adjustments including clinical presentation and stent type as well as in sensitivity analyses focusing on patients with ACS, those with AF as an indication for OAC, and those treated with DES (i.e., more than one-half of patients in the 1-month and >90% of patients in the longer term TAT group). Cautious interpretation of these findings is nonetheless required in light of the nonrandomized study design and the likely imperfect adjustment for unmeasured baseline confounders in this observational investigation.

The findings of this study complement the results of the ISAR-TRIPLE trial (18), which showed similar clinical outcomes at 9-month follow-up in patients treated with 6-week versus 6-month TAT following PCI with DES. The findings of ISAR-TRIPLE—in which TAT duration was randomly allocated and thromboembolic risk scores were well balanced between patient groups (18)—support a role for short TAT duration accounting for individual patient ischemic and bleeding risks. This concept is corroborated in the present real-world cohort, in which treatment guidance was guided by clinical judgment and was patient tailored, as reflected by the fact that three-quarters of patients with HAS-BLED scores ≥3 were discharged on short-term TAT, and a similar proportion of patients with HAS-BLED scores ≤2 were planned to receive longer term TAT (Figure 1C). Of note, 3-month treatment was prescribed in more than one-half of patients in the longer duration TAT group (i.e., shorter than the 6-month duration in ISAR-TRIPLE) (18). The maximal extent to which TAT can be safely reduced, also in conjunction with patient- and device-specific factors, requires further investigation.

Long-term exposure to TAT has been consistently linked to higher bleeding risk compared with less intensive regimens (14–16,28). In this study, shorter TAT duration was not associated with a reduction of clinically relevant bleeding complications throughout 1 year compared with more extended TAT treatment. This finding held true in landmark analyses following TAT cessation in the 1-month treatment group. Although it is not possible to disentangle medication-related from patient-related effects in this nonrandomized investigation, these findings likely relate to physician guidance, avoiding prolonged TAT in patients at increased bleeding risk. Focusing on the time frame between 1 and 12 months, it is reasonable to assume that higher patient-specific bleeding susceptibility in patients treated with 1-month TAT may have counterbalanced the protective effect of an earlier transition to less intensive regimens (mostly OAC plus antiplatelet monotherapy). This interpretation is nonetheless speculative and requires further investigation in a prospective fashion, accounting for different bleeding risks in conjunction with differing antithrombotic treatment durations.

The finding of nondiffering ischemic outcomes associated with 1-month TAT is reassuring but requires cautious interpretation, in view of the modest sample size and observational nature of this study. Notably, patients in the longer TAT group were likely at higher ischemic risk, as reflected by a higher frequency of ACS and particularly ST-segment elevation MI at baseline. In this context, the trend toward a higher MI rate in the long-TAT group within the first month (i.e., during the time frame when antithrombotic treatment modes did not differ between groups) (Online Table 1) suggests a possible effect of patient-related factors on outcomes. However, the small number of 30-day events and the nonrandomized study design limit the ability to draw definitive conclusions in this respect. It should also be noted that BMS were used in 25% of patients treated with 1-month TAT, although results did not differ after adjustment for stent type. The present findings are in line with evidence of comparable ischemic outcomes in orally anticoagulated patients when DAPT duration following PCI with DES was shortened to the duration generally recommended for BMS (18). Along the same lines, the ZEUS (Zotarolimus-Eluting Endeavor Sprint Stent in Uncertain DES Candidates) trial showed no signal of risk in patients who were at high bleeding and/or ischemic risk (including patients treated with OAC) despite shortening of DAPT to 30 days after PCI with new-generation DES (29). Evidence from nonanticoagulated patients appears to support shorter DAPT regimens following PCI with new-generation DES (30) and indicates similar risks for stent thrombosis for DES versus BMS between 1 and 12 months (31) or following DAPT cessation (26). Randomized trials adequately powered to assess ischemic outcomes, including the PIONEER AF-PCI (A Study Exploring Two Strategies of Rivaroxaban [JNJ39039039; BAY-59-7939] and One of Oral Vitamin K Antagonist in Patients With Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention; NCT01830543) and the REDUAL-PCI trial (Evaluation of Dual Therapy With Dabigatran vs. Triple Therapy With Warfarin in Patients With AF That Undergo a PCI With Stenting; NCT02164864), are currently investigating optimal combinations and durations of antiplatelet agents, warfarin, and novel OAC medications.

Omission of aspirin has been proposed as a means of mitigating the bleeding hazard of TAT (14–16). In the WOEST (What Is the Optimal Antiplatelet & Anticoagulant Therapy in Patients With Oral Anticoagulation and Coronary Stenting) trial, patients randomized to OAC plus clopidogrel versus TAT had lower rates of any bleeding but similar TIMI major bleeding, similar ischemic events, and reduced mortality (14). A large, nationwide registry reported higher rates of bleeding with TAT compared with OAC, alone or in combination with antiplatelet monotherapy, without difference in thromboembolic risk (16). Although these investigations provided valuable insights, they compared prolonged, 1-year TAT treatment (which is expected to increase bleeding complications) and, in contrast to the present study, assessed TAT in a binary fashion (i.e., not addressing differing TAT durations with subsequent transition to less intensive regimens, as is currently recommended). The combination of OAC plus clopidogrel may be considered as an alternative to TAT for selected patients with high bleeding and low ischemic risk (7); this therapeutic option could not be tested in the present study.

Study limitations

This study had several limitations attributable to its observational nature. First, the registry was not designed to evaluate clinical outcomes in relation to TAT; however, ischemic and bleeding events were prospectively defined outcome measures and were specifically evaluated during 1-year follow-up. The duration of TAT was not pre-defined but was individualized by physician judgment; our findings nonetheless reflect real-world practice, and treatment was tailored to individual patient risk, as is recommended in current guidelines. A notable limitation is the fact that that reported treatment durations pertain to prescription times at discharge, because the actual treatment duration was not consistently recorded. Although multivariate adjustments were performed to account for baseline differences, the effect of unmeasured baseline confounders cannot be excluded. The findings of the exploratory analyses are presented as hypothesis generating only; prospective studies are needed to definitively address the contribution of different antithrombotic treatment durations versus the impact of patient-specific ischemic and bleeding risks on clinical outcomes. This study could not assess the role of less intensive antithrombotic regimens (e.g., OAC plus antiplatelet monotherapy); ongoing trials are expected to address these issues. The present findings are applicable to TAT including clopidogrel, because the number of patients treated with more potent P2Y12 inhibitors was too small to allow a meaningful subanalysis; the impact of prasugrel as part of TAT regimens has been addressed in studies including more prasugrel-treated patients (28,32). The difference of prescribed TAT duration between groups was small; this may have limited the ability to detect differences in outcomes in relation to treatment duration.

Conclusions

Among patients with clinical indications for OAC undergoing PCI, 1-month TAT was associated with similar bleeding, ischemic, and net clinical outcomes compared with longer TAT durations throughout 1 year in this observational study. Reducing the duration of TAT to 1 month appears to be a reasonable option in patients with high bleeding risk. These findings require confirmation in prospective studies testing TAT regimens of pre-specified lengths tailored to individual patient ischemic and bleeding risks.

Perspectives

WHAT IS KNOWN? TAT is indicated for patients who require OAC who undergo PCI. Although triple therapy is recommended to be limited in duration in current consensus documents, there are few data addressing the optimal length of the combination of OAC plus DAPT.

WHAT IS NEW? In this observational study of 568 unselected patients undergoing PCI, we found similar ischemic events, bleeding events, and net clinical outcomes associated with abbreviated, 1-month duration versus more prolonged duration of triple therapy. These findings held true in analyses stratified for clinical presentation with stable CAD versus ACS and for interventions using DES versus BMS.

WHAT IS NEXT? Data from larger, prospective studies are needed to determine clinical outcomes in relation to pre-specified triple-therapy durations tailored to individual patient ischemic and bleeding risks and to assess the role of novel oral anticoagulant medications in this clinical setting.

Appendix

Appendix

For supplemental tables and a figure, please see the online version of this article.

Footnotes

Dr. Jüni is an unpaid steering committee or statistical executive committee member of trials funded by Abbott Vascular, Biosensors, Medtronic, and St. Jude Medical. Prof. Windecker has received research contracts to the institution from Abbott Vascular, AstraZeneca, Boston Scientific, Biosensors, Biotronik, Cordis, Eli Lilly, Medtronic, and St. Jude Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Koskinas and Räber contributed equally to this work.

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